Post-operative delirium (POD) and Post-operative cognitive dysfunction (POCD) are the two most common post-operative complications in older adults, and substantially increase peri-operative morbidity, mortality and cost of medical care. However, at present time, both POD and POCD are clinical phenomena and their neuropathogeneisis is largely unknown. This gap in knowledge has impeded development of targeted prevention and treatment strategies designed to address the underlying mechanisms of POD and POCD. Consistent with our central hypotheses that 2-Amyloid protein (A2) accumulation and neuroinflammation (e.g., microglia activation and brain cytokine accumulation) are linked with cognitive dysfunction and delirium, our preliminary studies have shown that high IL-6 levels and low A2 levels in the immediate pre-operative cerebrospinal fluid (CSF) are associated with POD and post-operative memory impairment, which suggest that high levels of A2 and cytokine in the brain may play a role in POD and POCD neuropathogenesis. Thus, the proposed research is aimed at determining the neuropathogenesis of POD and POCD by testing a hypothesis that high levels of A2 and IL-6 in the brain represent markers of brain vulnerability under peri-operative stress, leading to POD and POCD. We will employ bed-side cognitive tests and bench-side biochemistry analysis to accomplish three Specific Aims: (1) to investigate the association of pre-operative CSF A2 and IL-6 levels with POD measured 1, 2 and 3 days after scheduled total hip and knee replacement surgery conducted under spinal anesthesia, the CSF will be collected when spinal anesthesia is performed and therefore poses no added risk to the participants; (2) to determine the association of pre-operative CSF A2 and IL-6 levels with POCD measured 7 days, 3 months, and 1 year after surgery in the same population; (3) to perform feasibility studies of using positron emission tomographic imaging with Pittsburgh Compound B to measure brain amyloid amount and of using spinal catheter to collect immediate pre- and post-operative CSF. We will assess POD and POCD using validated and standardized methods, and measure CSF A2, IL-6 and cortisol levels with ELISA. The proposed project will provide important information regarding the neuropathogenesis of POD and POCD, and therefore is highly innovative and significant. The anticipated results will inform the design of targeted prevention and treatment strategies for POD and POCD and therefore have the potential to ultimately lead to better anesthesia and surgery care for older adults. Our proposal meets with the major mission of the National Institute of Aging to reduce the burdens of illness and disability in the elderly.